Breast cancer is the most frequently diagnosed malignancy in women and one of the top two causes of cancer-related deaths in women worldwide [Parkin D M, Fernandez L M. Use of statistics to assess the global burden of breast cancer. Breast Journal. January-February 2006; 12 Suppl 1:S70-80]. The incidence of breast cancer is estimated to reach 5 million women in the next decade.
Among women with primary breast cancer, 40 to 50% will develop metastatic disease, which despite active cytotoxic chemotherapy and newer biologic agents remains incurable [Smith I. Goals of treatment for patients with metastatic breast cancer. Seminars in Oncology. February 2006; 33(1 Suppl 2):S2-5]. As a result, treatment is aimed at palliation and improved quality of life, inhibition of disease progression and improvement in survival time.
The erythroblastic leukemia viral oncogene homolog (erb) family of tyrosine kinase inhibitors (TKIs) consists of 4 members: erbB-1 (EGFR [epidermal growth factor receptor]), erbB-2 (HER2, neu), erbB-3 (HER3) and erbB-4 (HER4). The erbB family of receptors is involved in cell proliferation, tumorigenesis, and metastasis and is abnormally expressed in multiple tumor types. The oncogenic role of erbB-2 has been most extensively documented in breast cancer, where gene amplification (as measured by positive fluorescence in situ hybridization [FISH]) or overexpression (as measured by immunohistochemistry [IHC] 3+) occurs in 25%-30% of breast cancers. Subjects with erbB-2-overexpressing breast cancers have been associated with more aggressive disease and poorer prognosis than for subjects whose tumors do not overexpress erbB-2 [Pegram M D, et al., The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer. Cancer Treatment & Research. 2000; 103:57 75].
Many different cytotoxic agents are currently available for the treatment of metastatic breast cancer (MBC), and multiple factors determine the choice of treatment. These include previous adjuvant therapy, tumor characteristics, subject characteristics, and subject preference. As anthracycline and taxanes are the most active cytotoxic agents in breast cancer, anthracycline/taxane-containing regimens are the mainstay of adjuvant therapy.
Capecitabine has been on the market since 1998, when it was the first oral chemotherapy approved by the FDA for the treatment of metastatic breast cancer [FDA. Prescribing Information for Xeloda® (capecitabine) U.S. Government; 2006]. Capecitabine (5′-deoxy-5-fluoro-N-[(pentyloxy)carboyl]-cytidine) is a fluoropyidine carbamate analog with antitumor activity. Capecitabine is used as monotherapy and in combination therapy regimens for the treatment and palliative management of various forms of cancer including colorectal and breast cancer. Despite its demonstrated clinical usefulness, there are a number of disadvantages associated with the use of capecitabine which can be dose-limiting and which may render patients unable to tolerate treatment using capecitabine. Adverse reactions commonly seen during systemic therapy using capecitabine, include diarrhea, stomatitis, nausea and vomiting, hand-and-foot syndrome, anemia, hyperbilirubinemia, dermatitis and alopecia. Other adverse effects associated with the systemic administration of capecitabine include constipation, abdominal pain, edema, decrease appetite, dyspnea, back pain, neutropenia, nail disorders, pyrexia, asthenia, fatigue, weakness, headache dizziness, anorexia, arthralgia, myaligia, neutropenic fever, cough, sore throat, leukopenia and thrombocytopenia.
The use of the antibody trastuzumab for breast cancer treatment has been described. However, breast cancer cells may become resistant to trastuzumab on the basis of extracellular domain (ECD) truncated erbB-2 receptor, that can no longer be recognized by the antibody [Xia, W. Truncated ErbB2 receptor (p95ErbB2) is regulated by heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 2004, 23:646-653], or because of coactivation of erbB-1 signaling [Rampaul, R S, et al, Clinical value of epidermal growth factor receptor expression in primary breast cancer. Adv Anat Pathol 2005, 12:271-273; Zaczek, A, et al., The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol 2005, 20:1005-1015].
What are needed are additional effective therapies for solid tumors and/or breast cancer.